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1.  Pump-Probe Imaging Differentiates Melanoma from Melanocytic Nevi 
Science Translational Medicine  2011;3(71):71ra15.
Melanoma diagnosis is clinically challenging; the accuracy of visual inspection by dermatologists is highly variable and heavily weighted toward false positives. Even the current gold standard of biopsy results in varying diagnoses among pathologists. We have developed a multiphoton technique (based on pump-probe spectroscopy) that directly determines the microscopic distribution of eumelanin and pheomelanin in pigmented lesions of human skin. Our initial results showed a marked difference in the chemical variety of melanin between nonmalignant nevi and melanoma, as well as a number of substantial architectural differences. We examined slices from 42 pigmented lesions and found that melanomas had an increased eumelanin content compared to nonmalignant nevi. When used as a diagnostic criterion, the ratio of eumelanin to pheomelanin captured all investigated melanomas but excluded three-quarters of dysplastic nevi and all benign dermal nevi. Evaluating architectural and cytological features revealed by multiphoton imaging, including the maturation of melanocytes, presence of pigmented melanocytes in the dermis, number and location of melanocytic nests, and confluency of pigmented cells in the epidermis, further increased specificity, allowing rejection of more than half of the remaining false-positive results. We then adapted this multiphoton imaging technique to hematoxylin and eosin (H&E)–stained slides. By adding melanin chemical contrast to H&E-stained slides, pathologists will gain complementary information to increase the ease and accuracy of melanoma diagnosis.
doi:10.1126/scitranslmed.3001604
PMCID: PMC3371363  PMID: 21346168
2.  A juvenile case of conjunctival atypical nevus 
Diagnostic Pathology  2013;8:64.
Virtual slides
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2973228795724608
Melanocytic nevi are the most common tumors of the conjunctiva, accounting for 28% of all neoplastic lesions. These tumors, despite their benign behavior, share some atypical histological features with nevi found in other anatomic sites like the genital and acral regions, globally designated as nevi with site-related atypia. Moreover, in children and adolescents, rapidly growing conjunctival nevi show sometimes worrisome histological patterns in association with a prominent inflammatory infiltrate that may lead to diagnostic problems. In this paper we describe a juvenile compound nevus characterized by marked melanocytic atypia and severe inflammation, which can be considered a rare case of juvenile conjunctival atypical nevus. The final diagnosis relied on morphological and immunohistochemical characterization of the large epithelioid melanocytic cells, and on the results of FISH analysis.
doi:10.1186/1746-1596-8-64
PMCID: PMC3662158  PMID: 23607499
3.  Combined nevi of the conjunctiva. 
PURPOSE: To report the clinical and histologic features of combined nevi of the conjunctiva, a type of nevus that is not uncommon in the skin but has rarely been reported in the conjunctiva. METHODS: Conjunctival nevi and melanomas from the files of the University of California, San Francisco, eye pathology laboratory were reviewed from 1984 to 1999 for the presence of features of both standard nevocytic nevi and blue nevi. Clinical histories and, when available, clinical photographs were obtained. RESULTS: Thirty-one combined nevi were discovered during the 15-year period between 1984 and 1999. One case before 1984 had been incorrectly diagnosed as a junctional nevus. The dendritic and spindle-shaped blue nevus cells had been overlooked because they were not recognized as distinct from the standard nevocytic nevus cells. The recognition of a blue as well as a brown color, a deep as well as a superficial component in the lesion, or a history of pigmentation since birth may help to establish the correct clinical diagnosis and prevent an unnecessarily deep surgical resection. Although growth of the lesion or "satellites" in some patients may favor a clinical diagnosis of melanoma, none of the lesions in this series were malignant. CONCLUSION: Despite a paucity of reports of combined nevi of the conjunctiva in the medical literature, this type of nevus--a combination of a nevocytic and a blue nevus--is common and has been overlooked in the past.
Images
PMCID: PMC1298259  PMID: 10703123
4.  Cystic Benign Melanosis of the Conjunctiva 
Cornea  2012;31(11):1273-1277.
Purpose
To report the clinical and histologic features of cystic benign melanosis.
Methods
This case series reports on the clinical and histopathologic features of three patients with enlarging cystic, brown pigmented conjunctival lesions.
Results
Slit lamp exam showed cystic melanotic lesions of bulbar conjunctiva. Histopathologic examination of the biopsy specimens showed epithelial lined cysts in the substantia propria, goblet cells, and secondary pigmentation of basilar keratinocytes.
Conclusions
Cystic benign melanosis, a unique conjunctival lesion, should be differentiated from cystic nevus and primary acquired melanosis (PAM).
doi:10.1097/ICO.0b013e31823d1ec4
PMCID: PMC3467456  PMID: 23044615
conjunctiva; benign melanosis; cystic melanosis; epithelial inclusion cyst; racial melanosis
5.  Correlation between dermoscopic and histopathological diagnoses of atypical nevi in a dermatology outpatient clinic of the Medical School of São José do Rio Preto, SP, Brazil* 
Anais Brasileiros de Dermatologia  2013;88(2):199-203.
BACKGROUND
The incidence of cutaneous melanoma is increasing worldwide. Since it is an aggressive neoplasm, it is difficult to treat in advanced stages; early diagnosis is important to heal the patient. Melanocytic nevi are benign pigmented skin lesions while atypical nevi are associated with the risk of developing melanoma because they have a different histological pattern than common nevi. Thus, the clinical diagnosis of pigmented lesions is of great importance to differentiate benign, atypical and malignant lesions. Dermoscopy appeared as an auxiliary test in vivo, playing an important role in the diagnosis of pigmented lesions, because it allows the visualization of structures located below the stratum corneum. It shows a new morphological dimension of these lesions to the dermatologist and allows greater diagnostic accuracy. However, histopathology is considered the gold standard for the diagnosis.
OBJECTIVES
To establish the sensitivity and specificity of dermoscopy in the diagnosis of pigmented lesions suspected of malignancy (atypical nevi), comparing both the dermatoscopic with the histopathological diagnosis, at the Dermatology Service of the outpatient clinic of Hospital de Base, São José do Rio Preto, SP.
METHODS
Analysis of melanocytic nevi by dermoscopy and subsequent biopsy on suspicion of atypia or if the patient so desires, for subsequent histopathological diagnosis.
RESULTS
Sensitivity: 93%. Specificity: 42%.
CONCLUSIONS
Dermoscopy is a highly sensitive method for the diagnosis of atypical melanocytic nevi. Despite the low specificity with many false positive diagnoses, the method is effective for scanning lesions with suspected features of malignancy.
doi:10.1590/S0365-05962013000200002
PMCID: PMC3750880  PMID: 23739709
Dermoscopy; Diagnosis; Nevus, pigmented
6.  CUTANEOUS TUMORS OF CHILDREN 
California Medicine  1957;86(1):1-7.
Nevi are the most common tumors of childhood. Pigmented nevi are classified into blue nevi, intraepidermal nevi, junction nevi, intradermal nevi (or common mole) and combination types. Cutaneous malignant disease in children is rare. Malignant melanoma is rare before puberty. Wholesale removal of benign pigmented nevi in children should be condemned. However, junction nevi located on the palms, soles, genitalia or waistline—that is, in areas subject to frequent trauma—should be excised.
Hemangiomas in infants are the most common tumors for which advice is sought. Not all hemangiomas regress spontaneously, and on occasion the persistence or progression of such a lesion may bring about life-long unsightly deformities. Therapy for this type of tumor is simple when given early in life. Hemangiomas involving the ears, nose, lips or eyelids should be treated at once, preferably within a month of the time they appear.
Images
PMCID: PMC1511978  PMID: 13383381
7.  Diagnosing Ocular Surface Squamous Neoplasia in East Africa 
Ophthalmology  2014;121(2):484-491.
Objective
To examine the reliability of clinical examination and in vivo confocal microscopy (IVCM) in distinguishing ocular surface squamous neoplasia (OSSN) from benign conjunctival lesions.
Design
Case-control study.
Participants
Sixty individuals with conjunctival lesions (OSSN and benign) and 60 age-matched controls with normal conjunctiva presenting to Kilimanjaro Christian Medical Centre, Moshi, Tanzania.
Methods
Participants were examined and photographed, and IVCM was performed. Patients with conjunctival lesions were offered excisional biopsy with histopathology and a human immunodeficiency virus (HIV) test. The IVCM images were read masked to the clinical appearance and pathology results. Images were graded for several specific features and given an overall categorization (normal, benign, or malignant). A group of 8 ophthalmologists were shown photographs of conjunctival lesions and asked to independently classify as OSSN or benign.
Main Outcome Measures
Comparison of the histopathology diagnosis with the clinical and IVCM diagnosis.
Results
Fifty-two cases underwent excisional biopsy with histopathology; 34 were on the OSSN spectrum, 17 were benign, and 1 was lymphoma. The cases and controls had comparable demographic profiles. Human immunodeficiency syndrome infection was more common in OSSN compared with benign cases (58.8% vs. 5.6%; odds ratio, 24.3, 95% confidence interval [CI], 2.8–204; P = 0.003). Clinically, OSSN lesions more frequently exhibited feeder vessels and tended to have more leukoplakia and a gelatinous appearance. Overall, the ophthalmologists showed moderate agreement with the histology result (average kappa = 0.51; 95% CI, 0.36–0.64). The masked grading of IVCM images reliably distinguished normal conjunctiva. However, IVCM was unable to reliably distinguish between benign lesions and OSSN because of an overlap in their appearance (kappa = 0.44; 95% CI, 0.32–0.57). No single feature was significantly more frequent in OSSN compared with benign lesions. The sensitivity and specificity of IVCM for distinguishing OSSN from benign conjunctival lesions were 38.5% and 66.7%, respectively.
Conclusions
In East Africa, conjunctival pathology is relatively common and can present significant diagnostic challenges for the clinician. In this study, neither clinical examination nor IVCM was found to reliably distinguish OSSN from benign conjunctival pathology because of an overlap in the features of these groups. Therefore, IVCM cannot currently replace histopathology, and management decisions should continue to rely on careful clinical assessment supported by histopathology as indicated.
doi:10.1016/j.ophtha.2013.09.027
PMCID: PMC3901930  PMID: 24321141
8.  DEK Expression in Melanocytic Lesions 
Human pathology  2011;42(7):932-938.
The diagnosis of malignant melanoma presents a clinical challenge and relies principally on histopathological evaluation. Previous studies have indicated that increased expression of the DEK oncogene, a chromatin-bound factor, could contribute to the development of melanoma and may be a frequent event in melanoma progression. Here, we investigated DEK expression by immunohistochemistry in a total of 147 melanocytic lesions, including ordinary nevi, dysplastic nevi, Spitz nevi, melanoma in situ, primary invasive melanomas, and metastatic melanomas. Most benign nevi (ordinary, dysplastic and Spitz nevi) were negative or exhibited weak staining for DEK with only 4 of 49 cases showing strong staining. Similar to benign nevi, melanoma in situ also demonstrated low levels of DEK expression. In contrast, the expression of DEK in primary invasive melanomas was significantly higher than benign nevi (p<0.0001). Moreover, DEK expression was significantly increased in deep melanomas (Breslow depth > 1mm) and metastatic melanomas as compared to superficial melanomas (Breslow depth ≤ 1mm) (p<0.05). Our findings indicate that DEK overexpression may be a frequent event in invasive melanomas, and further augmentation of DEK expression may be associated with the acquisition of ominous features such as deep dermal invasion and metastasis. These data suggest a role of DEK in melanoma progression.
doi:10.1016/j.humpath.2010.10.022
PMCID: PMC3162348  PMID: 21316078
DEK; benign nevi; invasive melanomas; metastatic melanomas; melanoma progression
9.  Germline mutations in BAP1 predispose to melanocytic tumors 
Nature Genetics  2011;43(10):1018-1021.
Common acquired melanocytic nevi are benign neoplasms that are composed of small uniform melanocytes and typically present as flat or slightly elevated, pigmented lesions on the skin. We describe two families with a new autosomal dominant syndrome characterized by multiple skin-colored, elevated melanocytic tumors. In contrast to common acquired nevi, the melanocytic neoplasms in affected family members ranged histopathologically from epithelioid nevi to atypical melanocytic proliferations that showed overlapping features with melanoma. Some affected patients developed uveal or cutaneous melanomas. Segregating with this phenotype, we found inactivating germline mutations of the BAP1 gene. The majority of melanocytic neoplasms lost the remaining wild-type allele of BAP1 by various somatic alterations. In addition, we found BAP1 mutations in a subset of sporadic melanocytic neoplasms showing histologic similarities to the familial tumors. These findings suggest that loss of BAP1 is associated with a clinically and morphologically distinct type of melanocytic neoplasm.
doi:10.1038/ng.910
PMCID: PMC3328403  PMID: 21874003
10.  Seborrheic Keratosis of the Conjunctiva: A Case Report 
Seborrheic keratosis is a benign epithelial neoplasia that occurs mainly in the skin of the eyelids and face. We describe a case of seborrheic keratosis of the conjunctiva confirmed by histopathology. A 72-year-old man presented with a recurrent conjunctival mass involving the nasal side of his right eye. Clinically, a diagnosis of conjunctival papilloma was made, and a mass excision was performed. The histopathological analysis evidenced a conjunctival-covering epithelium with papillomatous changes and irregular acanthosis, at the expense of a proliferation of basaloid cells. In addition, the lesion exhibited multiple pseudohorn cysts containing keratin. With the above findings, a diagnosis of conjunctival seborrheic keratosis was established. The occurrence of seborrheic keratosis on the conjunctiva is rare. In this case, seborrheic keratosis was confirmed by pathologic report despite its similar appearance with papilloma. Seborrheic keratosis should be considered in the differential diagnosis of conjunctival lesions.
doi:10.3341/kjo.2009.23.4.306
PMCID: PMC2789958  PMID: 20046694
Conjunctival mass; Seborrheic keratosis; Papilloma
11.  Prognostic value of clinical and histopathological parameters in conjunctival melanomas: a retrospective study 
Aim: To determine prognostic factors for recurrence of disease and tumour related mortality in patients with conjunctival melanoma.
Methods: A retrospective analysis of clinical and histopathological data of 69 patients with histologically verified conjunctival melanoma.
Results: As univariate analysis showed, significant risk factors for the development of recurrence were: irregular pigmentation (RR = 2.0, p = 0.0007), incomplete surgical excision (RR = 3.5, p = 0.008), tumour invasion deeper than in substantia propria (RR = 3.9, p = 0.008), and presence of epithelioid tumour cells (RR = 2.9, p = 0.05). For tumour related mortality a significantly increased risk was found for tumour location in palpebral conjunctiva, caruncle, plica, or fornices (RR = 5.9, p = 0.001), for tumour infiltration deeper than the substantia propria (RR = 5.5, p = 0.001), for incomplete surgical excision (RR = 4.4, p = 0.05), and for nodular or mixed (nodular and superficial) growth pattern of the tumours (RR = 1.2, p = 0.002). The use of an adjuvant therapy for the surgical excision of the melanomas had no statistically significant influence upon the development of recurrent disease nor upon the tumour related mortality.
Conclusion: These data present similar clinical and histopathological risk factors for patients with conjunctival melanoma as reported previously. The present study also addresses the failure of retrospective studies on conjunctival melanoma to prove the efficacy of a supplementary therapy to surgical excision.
PMCID: PMC1771018  PMID: 11815341
12.  Clinical and Dermoscopic Features of 88 Scalp Nevi in 39 Children 
The British journal of dermatology  2011;165(1):137-143.
Summary
Background
Paediatric scalp nevi may represent a source of anxiety for practitioners and parents, as the clinical and dermoscopic features of typical nevi have yet to be defined. Prompted by concern about the large size, irregular borders, and colour variation of scalp nevi, clinicians and parents may request unnecessary excision of these nevi.
Objective
The purpose of this study is to establish the typical clinical and dermoscopic patterns of scalp nevi in children younger than 18 years old to help optimize clinical care and management.
Methods
Scalp nevi were imaged with a camera (Canon Rebel, XSi) and dermoscopic attachment (3Gen, Dermlite Foto, 30mm lens) to the camera. The clinical and dermoscopic images were reviewed and analyzed. Both acquired and congenital scalp nevi were included but were not further differentiated from each other.
Results
We obtained clinical and dermoscopic images of 88 scalp nevi in 39 Caucasian children. Two subjects had received chronic immunosuppressive medication. Nineteen children have had a family history of melanoma. Males (18/39 subjects, 46%) possessed 68% (60 nevi) of scalp nevi imaged. Younger (<10 years old) subjects (24/39 subjects, 62%) possessed 42% (37 nevi) of scalp nevi. The main clinical patterns included eclipse (n=18), cockade (n=3), solid brown (n=42), and solid pink (n=25) nevi. Solid-coloured nevi showed the following dermoscopic patterns: globular (57%), complex (reticular-globular) (27%), reticular (9%), homogenous (6%), and fibrillar (1%). The majority of nevi had a unifying feature—perifollicular hypopigmentation, which caused the appearance of scalloped, irregular borders if occurring on the periphery, or variegation in pigmentation, if occurring within the nevi.
Conclusions
Older subjects and males tend to harbour a larger proportion of scalp nevi. The main clinical patterns include solid-coloured and eclipse nevi. The most common dermoscopic pattern of scalp nevi is the globular pattern. Perifollicular hypopigmentation is a hallmark feature of signature scalp nevi. Dermoscopy is a non-invasive tool in the evaluation of cutaneous melanocytic lesions in children and may decrease the number of unnecessary excisions.
doi:10.1111/j.1365-2133.2011.10297.x
PMCID: PMC3125493  PMID: 21410662
13.  Pigmented Lesions in Children 
Seminars in Plastic Surgery  2006;20(3):169-179.
ABSTRACT
Pigmented lesions in childhood can pose significant diagnostic and therapeutic challenges. This article examines the most common pigmented lesions encountered in childhood. Special emphasis is placed on the diagnosis and management of congenital melanocytic nevi, acquired melanocytic nevi, clonal nevi, halo nevi, atypical melanocytic nevi, Spitz nevi, recurrent nevi, childhood melanoma, blue nevi, speckled lentiginous nevi, and other melanocytic nevi such as nevus of Ota and nevus of Ito. Proper diagnosis and an understanding of the natural history of pigmented lesions in children are essential for successful outcomes.
doi:10.1055/s-2006-949120
PMCID: PMC2884762
Pigmented nevus; pediatric; Spitz nevus; congenital nevus; melanoma
14.  Conjunctival Stromal Tumor 
Ophthalmology  2011;119(4):682-687.
Purpose
To describe the clinical, histopathologic, immunohistochemical, and ultrastructural features of a case series of benign stromal tumors in the bulbar conjunctiva.
Design
Observational case series.
Participants
Four patients with a conjunctival lesion that were classified histologically as low grade stromal tumors consisting of spindle-shaped cells with occasional pseudonuclear inclusion and multinucleated cells in a partly myxoid matrix.
Methods
Four cases of low grade conjunctival stromal tumors were retrospectively identified in an ophthalmic pathology laboratory database. Patients’ records were analyzed for demographic data, clinical appearance and the post-operative course. Formalin-fixed paraffin-embedded specimens were routinely processed and stained with hematoxylin and eosin (H&E) and periodic acid Schiff (PAS). Immunohistochemical stains for vimentin, S100, CD34, SMA (smooth muscle actin), CD68, and factor XIIIa were performed. Transmission electron microscopy (TEM) was performed on three of the cases.
Main Outcome Measures
Histopathologic evaluation (including immunostains and TEM) and clinical correlation.
Results
All four tumors occurred in the bulbar conjunctiva of patients between 41 to 53 years of age. None of the patients developed recurrence after excisional biopsy. Histologically, all tumors exhibited spindle-shaped cells with pseudonuclear inclusions and occasional multinuclear cells. Mitotic figures were not observed. The stroma appeared myxoid to collagenous. Immunohistochemical stains were positive for CD34, vimentin, and focally for CD68, but were negative for S100 and SMA.
Conclusions
We propose to classify these benign lesions which share distinct histopathologic features as “conjunctival stromal tumor (COST)”. A reactive/inflammatory component needs to be considered in the pathogenesis of this lesion.
doi:10.1016/j.ophtha.2011.09.024
PMCID: PMC3314726  PMID: 22200094
15.  Comparative genomic hybridization for the diagnosis of melanoma 
Despite advancements in protocols, a subset of melanocytic lesions continues to pose diagnostic challenges. This is particularly true in the pediatric population where certain congenital nevi mimic melanoma. Recently, comparative genomic hybridization (CGH) has been utilized to support diagnoses of melanocytic lesions based on DNA copy number changes. Because distinct differences in copy number changes have been shown to occur in malignant melanoma and benign nevi, CGH can be a useful adjunct when diagnosis based on histology alone is indeterminate. The authors discuss the benefits of using CGH to aid in the diagnosis of melanocytic lesions that are difficult to characterize as malignant or benign based on clinical and histologic features alone. This paper presents a brief clinical report and review of the literature. A 13-year-old Caucasian male presented to an academic tertiary care medical center after a shave biopsy unexpectedly revealed malignant melanoma with positive deep margins. Following complete excisional biopsy, the diagnosis of malignant melanoma with depth of 0.92 mm was confirmed, both by the home institution's pathologist and by consultant dermatopathologists at two separate academic tertiary medical centers. Sentinel lymph node biopsy revealed a small focus of metastatic melanoma, this lead to a left-sided modified radical neck dissection. All nodes removed were negative for disease, and surgical and postsurgical care was uncomplicated. Before proceeding with interferon therapy, CGH was performed on the tissue from the primary lesion. Other than a slight amplification of chromosome 16p, no other aberrations were detected favoring a benign lesion. Ultimately, the diagnosis was amended to compound melanocytic nevus of the nose with benign nevus cell rest in the sentinel node. While histopathologic evaluation is the current gold standard for the diagnosis of melanoma, there are many cases where it is inaccurate. The use of CGH in the evaluation of histologically equivocal lesions may allow certain patients to avoid invasive procedures and associated morbidities. The authors propose that, in these select diagnostically challenging cases, tissue analyses by CGH may be beneficial before proceeding to more invasive procedures such as sentinel node biopsy and complete lymphadenectomy.
doi:10.1007/s00238-009-0369-9
PMCID: PMC2837230  PMID: 20234825
Melanoma; Diagnosis; Nevus; Nevi; Comparative genomic hybridization
16.  Imaging Microscopic Pigment Chemistry in Conjunctival Melanocytic Lesions Using Pump-Probe Laser Microscopy 
Purpose.
To report the application of a novel imaging technique, pump-probe microscopy, to analyze patterns of pigment chemistry of conjunctival melanocytic lesion biopsies.
Methods.
Histopathologic specimens of eight previously excised conjunctival melanocytic lesions were analyzed with pump-probe microscopy. The technique uses a laser scanning microscope with a two-color pulsed laser source to distinguish hemoglobin, eumelanin, and pheomelanin pigment based on differences in transient excited state and ground state photodynamics. The pump-probe signatures of conjunctival melanins were compared with cutaneous melanins. The distributions of hemoglobin, eumelanin, and pheomelanin were analyzed, and pump-probe images were correlated with adjacent hematoxylin and eosin (H&E)-stained sections.
Results.
The pump-probe signatures of conjunctival melanins are similar, but not identical to cutaneous melanins. In addition, there are qualitative and quantitative differences in the structure and pigment chemistry of conjunctival benign nevi, primary acquired melanosis of the conjunctiva (PAM), and conjunctival melanomas. The pump-probe images correlated well with histopathologic features observed in the adjacent H&E-stained sections, and provided a label-free means of discerning conjunctival anatomic features and pathologic benign or malignant tissue.
Conclusions.
Pump-probe laser microscopy shows promise as an adjuvant diagnostic tool in evaluation of ocular melanocytic lesions based on morphologic correlation with the histopathology results and pigment chemistry. This initial study suggests systematic differences in pigmentation patterns among conjunctival benign nevi, primary acquired melanosis, and melanomas. In addition, pump-probe microscopy has the potential for use as a noninvasive “in vivo” optical biopsy technique to aid clinical and surgical management of conjunctival melanocytic lesions.
Using pump-probe microscopy, a multiphoton technique that images absorptive pigments, we analyzed the microscopic distribution of melanins in biopsy sections of conjunctival melanocytic lesions, and found differences among conjunctival benign nevi, primary acquired melanosis, and melanomas.
doi:10.1167/iovs.13-12432
PMCID: PMC3805089  PMID: 24065811
conjunctival melanoma; primary acquired melanosis; benign conjunctival nevus; pump-probe microscopy; multiphoton microscopy
17.  On the clinical significance of cutaneous melanoma's precursors 
We can identify three main groups of cutaneous pigmented lesions that could be represented as melanoma precursors: (a) congenital melanocytic nevi, (b) dysplastic or atypical nevi, and (c) acquired melanocytic nevi. The occurrence of melanoma in small and intermediate congenital melanocytic nevi is very uncommon, but there is a high risk in large congenital melanocytic nevi, in particular those arising in the so-called “bathing trunk” distribution. It is very important to distinguish the familial dysplastic nevus syndrome, which is a strong risk factor for cutaneous melanoma, from not familial (sporadic) dysplastic nevus, in which the risk for melanoma would depend on the total number of melanocytic nevi, phototype, and on the relationship to environmental factors.
doi:10.4103/2229-5178.96690
PMCID: PMC3481870  PMID: 23130279
Congenital nevus; dysplastic nevus; melanoma
18.  Squamous cell papilloma of the conjunctiva due to human papillomavirus (HPV): presentation of two cases and review of literature 
Purpose
We describe two patients with squamous cell papilloma of the conjunctiva due to human papilloma virus (HPV) and review the literature.
Patients and methods
Two patients with conjunctival tumors were examined and treated in the University Eye Clinic and diagnosed in the University Pathology Department, University Hospital of Ioannina, Greece. The first patient was a 48-year-old man presenting with an extended papillomatous lesion in bulbar conjunctiva covering part of the cornea of his right eye. The second patient was a 24-year-old man presenting with a polypoidal papillomatous lesion on the caruncle of his right eye. The two lesions were removed surgically, cryotherapy was applied to the adjacent conjunctiva, and topical mitomycin-C was used. The amniotic membrane was used to restore the conjunctival defect in the first patient. The two removed lesions were sent to the Pathology Department for histopathological examination. Immunohistochemistry, DNA in situ hybridization, and polymerase chain reaction (PCR) analysis were performed.
Results
In the first patient, histopathology showed the presence of a benign squamous papilloma with koilocytosis. DNA in situ hybridization with broad-spectrum probes showed that this patient was positive for HPV DNA. In the second patient, histopathology showed the presence of a squamous papilloma with mild dysplasia and koilocytosis. Immunohistochemical analysis was positive for HPV protein and p16 protein. DNA in situ hybridization with broad-spectrum probes showed that the patient was positive for HPV DNA. PCR analysis showed the presence of HPV 6. According to morphological and molecular findings, both patients were diagnosed with squamous cell papilloma due to HPV.
Conclusion
HPV can infect the ocular surface. According to clinical results, the ophthalmologist in cooperation with the pathologist can recommend appropriate laboratory examinations to confirm the diagnosis and successfully treat conjunctival papillomas.
doi:10.2147/OPTH.S34999
PMCID: PMC3460712  PMID: 23055678
conjunctiva; papilloma; human papillomavirus; koilocytosis; in situ hybridization; polymerase chain reaction
19.  Necrobiotic xanthogranuloma and chronic lymphocytic leukemia of the conjunctiva masquerading as scleritis and uveitis 
This report describes a unique case of coexisting necrobiotic xanthogranuloma and chronic lymphocytic leukemia in a patient presenting with scleritis and uveitis. A 53-year-old Caucasian man diagnosed with anterior uveitis and scleritis for the prior year was referred to our uveitis clinic for further evaluation. Prior uveitis/scleritis workup performed by the referring ophthalmologist was negative. Examination demonstrated unilateral uveitis and posterior scleritis along with bilateral conjunctival lesions. Incisional biopsy of the conjunctiva was carried out. The excised tissue was sent fresh for histopathologic studies. Slit-lamp examination revealed bilateral yellow-white bulbar conjunctival lesions, 1+ conjunctival injection OU, stellate keratic precipitates OS with 25 cells per high-powered field. Funduscopic examination was significant for subretinal fluid OS. Conjunctival biopsy revealed necrobiotic xanthogranuloma and chronic lymphocytic leukemia. Systemic workup demonstrated paraproteinemia consistent with necrobiotic xanthogranuloma and a complete blood count consistent with leukemia. This case demonstrates an atypical presentation of necrobiotic xanthogranuloma and concomitant chronic lymphocytic leukemia presenting in the form of uveitis, scleritis, and conjunctival infiltration. Masquerade syndromes, such as necrobiotic xanthogranuloma and leukemia, must be kept in mind when treating patients with uveitis or scleritis with negative workups.
doi:10.2147/OPTH.S35743
PMCID: PMC3526909  PMID: 23271884
necrobiotic xanthogranuloma; chronic lymphocytic leukemia; uveitis; scleritis; masquerade syndrome
20.  Recurrence of Mycosis Fungoides on Multiple Melanocytic Nevi: A Case Report and Review of the Literature 
Case Reports in Dermatology  2012;4(1):92-97.
Melanocytic nevi represent a widespread cutaneous finding. Nevertheless, the presence of mycosis fungoides and melanocytic nevi in the same location is an extremely rare event. We report the case of a patient affected by mycosis fungoides and treated with PUVA therapy, with complete remission of the disease. Eight years after therapy discontinuation, he presented epidermal scaling and an erythematous perinevic halo on 3 old melanocytic lesions, the clinical aspect of which was highly suggestive for Meyerson nevi. The histological and immunohistochemical examination of an excised melanocytic lesion revealed histological features consistent with the diagnosis of mycosis fungoides superimposed on junctional melanocytic nevi. The finding of patches of mycosis fungoides superimposed on melanocytic nevi is a rare event; the confounding clinical appearance with eczematous changes around a pre-existing nevus may recall the halo dermatitis known as Meyerson phenomenon; this highlights the importance of clinical and histological examination to make the correct diagnosis of dermatological diseases.
doi:10.1159/000337750
PMCID: PMC3362184  PMID: 22649337
Mycosis fungoides; Melanocytic nevi; Halo phenomenon; PUVA therapy
21.  USE OF FLUORESCENCE IN-SITU HYBRIDIZATION (FISH) TO DISTINGUISH INTRANODAL NEVUS FROM METASTATIC MELANOMA 
With the increase in sentinel lymph node biopsies in melanoma patients, pathologists are frequently confronted with small deposits of morphologically bland melanocytes in the node, which occasionally cannot be readily classified as benign nodal nevi or melanoma. As most melanomas harbor characteristic chromosomal aberrations which can be used to distinguish it from benign nevi, we used fluorescence in-situ hybridization (FISH) with markers for three regions on chromosome 6 and one on chromosome 11 to determine the presence of chromosomal aberrations in sentinel lymph node specimens with small foci of melanocytes that had been diagnosed as metastatic melanoma or nodal nevi by histopathology. 59 tissue samples from 41 patients (24 lymph node metastases, 17 with nodal nevi, and 18 of the available corresponding primary melanomas) were analyzed by FISH. 20 of 24 (83%) cases diagnosed as metastatic melanoma showed aberrations by FISH. Of the four negative cases, three were unequivocal melanoma metastases, while one on re-review was histopathologically equivocal. Of the 17 nodal nevi one (6%) also showed aberrations by FISH, while the remainder were negative. Multiple aberrations were present in the positive case, some of which were also found in the corresponding primary tumor, identifying this case as a deceptively bland melanoma metastasis that had been misclassified by histomorphology. Our data indicate that FISH is a useful adjunct tool to traditional methods in the diagnostic workup of deposits of melanocytes in the lymph node that are histopathologically ambiguous.
doi:10.1097/PAS.0b013e3181c805c4
PMCID: PMC2831773  PMID: 20087158
22.  Prognostic factors in primary malignant melanoma of the conjunctiva: a clinicopathological study of 256 cases. 
A series of 256 consecutive cases of invasive primary conjunctival malignant melanomas was examined to identify clinical and histopathological prognostic factors. The follow up period varied between 0.3 and 45.9 years (mean 9 years, median 6.3 years). The 5 year survival rate was estimated at 82.9%, the 10 year survival rate at 69.3%. Multiple regression analysis with the Cox proportional hazards model was used to assess sex, age, and a number of baseline features of conjunctival malignant melanoma as possible prognostic factors influencing melanoma related mortality. In assessing each potential prognostic factor, the effects of all other factors were taken into account in the modelling process. Tumours in unfavourable locations--that is, those involving the palpebral conjunctiva, fornices, plica, caruncle, and lid margins, were associated with 2.2 times higher mortality compared with (epi)bulbar melanomas. Patients with mixed cell type tumours had about three times higher mortality compared with those with pure spindle cell melanomas, and histological evidence of lymphatic invasion by tumour cells was also a prognostic feature, carrying a fourfold increase in the death rate. Multifocal tumours were associated with a fivefold increase in mortality among those with tumours in favourable (epi)bulbar locations, but were not prognostic in patients with melanomas in unfavourable sites. The death rate was significantly higher in those with initial tumour thickness of more than 4 mm, but only among patients with unfavourably located melanomas. Sex, age, and clinical origin of the tumour (primary acquired melanosis, pre-existing naevus, or de novo) were not useful prognostic indicators in this study.
PMCID: PMC504757  PMID: 8199108
23.  The ultrastructure of conjunctival melanocytic tumors. 
The ultrastructure of conjunctival melanocytic lesions in 49 patients was evaluated to find significant differences between benign and malignant cells. The patients studied included 9 with benign epithelial (racial) melanosis, 2 with pigmented squamous cell papillomas, 16 with conjunctival nevi, 18 with primary acquired melanosis, and 11 with invasive nodules of malignant melanoma. In benign epithelial melanosis, dendritic melanocytes were situated along the basement membrane region of the conjunctival epithelium, with one basilar dendritic melanocyte lodged among every five or six basilar keratinocytes. The dendritic melanocytes extended arborizing cellular processes between the basilar and among the suprabasilar keratinocytes, which manifested considerable uptake of melanin granules into their cytoplasm. The benign dendritic melanocytes possessed nuclei with clumped heterochromatin at the nuclear membrane, small, tightly wound nucleoli, and large, elongated, fully melaninized melanin granules. In two patients with benign hyperplasia of the dendritic melanocytes, occasional dendritic melanocytes were located in a suprabasilar position, but were always separated from each other by keratinocytes or their processes. In the two black patients with benign pigmented squamous papillomas, the benign dendritic melanocytes were located hapharzardly at all levels of the acanthotic epithelium and not just along the basement membrane region. Melanin uptake by the proliferating keratinocytes was minimal. In benign melanocytic nevi of the conjunctiva, nevus cells within the intraepithelial junctional nests displayed a more rounded cellular configuration; short villi and broader cellular processes suggestive of abortive dendrites were found. The nuclear chromatin pattern was clumped at the nuclear membrane, but the nucleoli were somewhat larger than those of benign dendritic melanocytes in epithelial melanosis. The melanosomes were smaller and rounder than those in dendritic melanocytes and exhibited more haphazard arrangements of the melanofilaments, which were only partially melaninized. Mitochondria were more numerous than in dendritic melanocytes, and monoribosomes predominated over polyribosomes. Cytoplasmic filaments were inconspicuous. Cells in the immediate subepithelial connective tissue zone had features identical to those of the cells within the junctional nests. Smaller, lymphocytoid cells with less numerous and more rudimentary melanosomes were found in the middle and deeper portions of the lesions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMCID: PMC1298677  PMID: 6398936
24.  Systemic interferon-alpha (IFN-alpha) treatment leads to Stat3 inactivation in melanoma precursor lesions. 
Molecular Medicine  1999;5(1):11-20.
BACKGROUND: In the setting of familial melanoma, the presence of atypical nevi, which are the precursors of melanoma, is associated with a nearly 100% risk of developing primary melanoma by age 70. In patients with sporadic melanoma, it is estimated that 40-60% of melanomas develop in contiguous association with atypical nevi. Currently, the only way to prevent atypical nevi from progressing to melanoma is to monitor and excise them as soon as they exhibit changes in their clinical features. Activation of the transcription factor, Stat3, has been linked to abnormal cell growth and transformation as well as to interferon alpha (IFN-alpha)-mediated growth suppression in vitro. MATERIALS AND METHODS: To determine whether IFN-alpha, used for adjuvant therapy of high-risk, resected melanoma, induces changes in Stat3 in atypical nevi, patients with a clinical history of melanoma who have multiple atypical nevi were treated for 3 months with low-dose IFN-alpha. Thereupon, the new technology of microscopic spectral imaging and biochemical assays such as electrophoretic mobility shift assays (EMSAs) and immunoblot analysis were used for the study of atypical nevi, obtained before and after IFN-alpha treatment. RESULTS: The results of the investigations provided evidence that, as a result of systemic IFN-alpha treatment, Stat1 and Stat3, which are constitutively activated in melanoma precursor lesions, lose their ability to bind DNA, and as shown in the case of Stat3, become dephosphorylated. CONCLUSIONS: Unlike primary and metastatic melanomas, melanoma precursor lesions cannot be established as cell cultures. Thus, the only way to explore pathways and treatment regimens that might help prevent progression to melanoma is within the context of a melanoma precursor lesion study conducted prospectively. The findings presented here suggest that down-regulation of the transcription factors Stat1 and Stat3 by systemic IFN-alpha treatment may represent a potential pathway to prevent the activation of gene(s) whose expression may be required for atypical nevus cells to progress to melanoma.
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PMCID: PMC2230371  PMID: 10072444
25.  Pigmentary Nevi on Face Have Unique Patterns and Implications: The Concept of Blaschko's Lines for Pigmentary Nevi 
Indian Journal of Dermatology  2012;57(1):30-34.
Background:
Nevi are proposed to reflect the mosaicism and thus generally follow the different archetypal patterns of mosaicism. Blaschko's lines are the most common pattern of mosaicism. There have been many attempts to elucidate the Blaschko's lines on face from the distributional patterns of different nevi, but studies that evaluated exclusively pigmentary nevi are sparse. Aims: This study attempted to evaluate the patterns followed by different pigmentary nevi on face and utilized this to elucidate the pattern of embryological pigmentation on face.
Materials and Methods:
Spatial parameters like shape, orientation, and distribution patterns of different flat pigmentary nevi on face were analyzed and graphically drawn on human facial diagram. This was compared with existing facial Blaschko's lines. All cases of palpable pigmented nevi like congenital and giant melanocytic nevi and nevus spilus were excluded.
Results:
A total of 68 cases of pigmentary nevi on face (male-39, female-29) were examined. The shape and distribution lines were found to have a close similarity with Blaschko's lines on face with distinct differences.
Conclusions:
The concept of facial embryonic pigmentary ‘segment’, ‘unit’ and existence of separate Blaschko's lines for facial pigmentary nevi is conceived. Some insight into the pathogenesis of Blaschko's lines is also proposed in this study.
doi:10.4103/0019-5154.92673
PMCID: PMC3312653  PMID: 22470205
Blaschko's lines; distributional patterns; embryonic pigmentary segments; embryonic pigmentary units; face; mosaicism; pigmentary nevi

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